Bioadhesive polymeric nanoparticles or microparticles have been considered as promising particulate systems for the delivery of many compounds, including therapeutic molecules. The bioadhesive properties of these systems offer the possibility of creating a strong interaction and prolonged contact with the mucosal surfaces resulting in a significant increase drug absorption and improvement of patient compliance. Different studies and reviews describe the beneficial applications for buccal, nasal, ocular, oral, rectal and vaginal routes and provide examples of what can be achieved in vivo when using bioadhesive formulations.
Buccal bioadhesive microparticles and nanoparticles allow achieving local drug release in the mucosa. Within the oral cavity, it has been described the treatment of toothache, bacterial and fungal infections, aphthous ulcers, lichen planus, inflammation and dental stomatitis. A great number of studies have reported the use of buccal delivery systems for controlled release of drugs, such as fentanyl, denbufylline, zinc sulfate, chlorhexidine and theophylline. Intranasal mucoadhesive microspheres based on bioadhesive polymers such as chitosan, hyaluronic acid, and other polymers, enhance drug bioavailability [1-3] including desmopressin. Similarly, these systems enhance the oral bioavailability of biologically active molecules such as calcitonin. Further, bioadhesive microcarriers and nanocarriers were applied for the local application of many drugs in ophthalmology where they could prolong the drug release and did not produce the sensation of a foreign body or visual blurring. Mucoadhesive nanoparticles or microparticles have been also applied for local delivery strategies including skin delivery purposes, or to hair follicle. A new approach for the preparation of mucoadhesive microparticles has been considered as an innovative vaginal delivery system for econazole nitrate in the treatment of Candida albicans. One of the most interesting areas of research within the field of bioadhesive microparticles and nanoparticles has been focused on the mucosal vaccination and immunotherapy to enhance the induction of antibody responses in serum, as well as local and distal mucosal secretions. Significant advantages in using such an approach include ease of administration and the generation of both systemic and mucosal immunities.
Many bioadhesive polymers have been described to be applied to obtain bioadhesive particulate systems include polyacrylic acid (PAA), polyvinyl alcohol (PVA), cellulose derivatives and sodium alginate. Various copolymers of acrylic acid, such as acrylic acid/polyethylene glycol monomethyl ether copolymer and acrylic acid-2 ethylhexyl acrylate copolymer have also been studied. PAA, chitosan and its derivatives, hydroxypropylcellulose (HPC), PVA, gelatine, carrageenan, sodium carboxymethylcellulose (NaCMC), and hyaluronic acid, have been proved to interact with buccal mucosa.
Other promising bioadhesive polymers are those commercialized by International Specialty Products (ISP) under trademark GANTREZ®, i.e., poly methyl vinyl ether-co-maleic anhydride (PVM/MA) copolymers, that have been applied as adhesives, binder, fixatives, mucoadhesive for oral delivery strategies, buccal adhesive strategies, transdermal delivery systems and other cosmetic applications such as hair styling products. GANTREZ® copolymers include:                GANTREZ® AN copolymers, the anhydride form, which are supplied as a water-insoluble white powder that can be easily hydrolyzed to produce a transparent solution of the water-soluble free acid (GANTREZ® S);        GANTREZ® S copolymers, the free acid form, which are supplied in solution or in powder form;        GANTREZ® MS copolymers, a mixed salt of sodium/calcium PVM/MA copolymers, which are supplied as a powder, which can be slowly hydrolyzed in water, and        GANTREZ® ES copolymers, the half ester form of different alkyl chain lengths and molecular weights of PVM/MA copolymer, namely GANTREZ® ES 225 (monoethyl ester), GANTREZ® ES 425 (monobutyl ester) and GANTREZ® ES335I (isopropyl ester); these copolymers are water-insoluble but they are water-soluble when neutralized by bases in aqueous solution, and they are supplied as alcoholic solutions.        

Synthetic PVM/MA copolymers have very different applications. By illustrative, GANTREZ® AN copolymers are widely used as a thickener and flocculant, dental adhesive, excipient in oral tablets, excipient in transdermal patches, etc. In addition, the use of these copolymers for the controlled release of drugs and, in matrix forms, for the topical release of drugs in the eye as well as in the fabrication of bioadhesive microparticles or nanoparticles for drug delivery purposes or mucosal vaccination [4-5] has been reported. GANTREZ® S copolymers are used in toothpastes and mouthwashes, mainly as adhesive polymer for buccal hygiene products for the prolonged delivery of antimicrobial agents. GANTREZ® MS copolymer is used in denture adhesives, ostomy adhesives and in topical carriers for mucosal applications; micro- and nanoparticles based on GANTREZ® MS copolymer for local buccal cavity delivery purposes have been reported. GANTREZ® ES copolymers are used in enteric film coating agents and in ostomy adhesives; microparticles based on n-hexyl half ester of PVM/MA copolymer containing ketorolac tromethamine having an average diameter of 100-150 μm have been reported [6] although the eventual application of said microparticles is limited because they are normally degrade in vitro over a period of 4-5 days.
Many investigations have used PVM/MA copolymers to obtain micro- or nanoparticulate systems.
Nanosystems based on GANTREZ® AN copolymers are mainly obtained by the solvent displacement method. In this context, it has been reported the desolvatation of the PVM/MA copolymer in acetone with a hydroalcoholic phase followed by cross-linking of the nanoparticles formed with cross-linkers (e.g., polyamines or proteins). The stability in aqueous media of these nanosystems is quite short due to the hydrolysis of the GANTREZ® AN copolymer to GANTREZ® S copolymer which is water soluble. In an aqueous medium, said nanoparticles can be dissolved quite rapid. The stabilization of GANTREZ® AN nanosystems in aqueous medium needs a chemical modification and functionalization of the PVM/MA copolymer with a cross-linking agent (cross-linker), for example, a polyamine compound such as spermidine or spermine (although this coupling reaction needs at least 20 h under certain conditions), a diamine compound such as the toxic 1,3-diaminopropane (DP), or an immunogenic molecule such as bovine serum albumin (BSA). The addition of DP only weakly enhances the stability of GANTREZ® AN nanoparticles in phosphate buffered saline (PBS) [7]. Other disadvantages of cross-linking PVM/MA nanoparticles include the significant increase in the nanoparticles size and the dramatic decrease of the bioadhesive capacity of the nanosystems. In order to enhance the bioadhesive capacity of the GANTREZ® AN nanoparticles, said nanoparticles can be modified by hydrosoluble polymers such as poly ethylene glycols (PEG). However, this approach is accomplished with some drawbacks such as, for example, the modification of maleic anhydride copolymers with a hydroxyl containing compound to form ester derivatives need a high temperature and aggressive acidic conditions, and the use of hydrophilic PEG (low OH content) may transform the GANTREZ® AN copolymer into a more hydrosoluble derivative and thus decrease the stability in aqueous media of the resulting nanoparticles.
Further, some difficulties have been reported in relation with the ability of GANTREZ® AN nanoparticles for incorporating hydrosoluble drugs in the organic phase of the polymer (a solution of GANTREZ® AN in acetone). As it is known, hydrosoluble drugs are not soluble in acetone and may form big size crystals that can interfere with the formation of nanoparticles once a hydroalcoholic solution is added to precipitate GANTREZ® AN in the form of nanosystems. For that reason, a hydrosoluble drug, 5-fluorouridine (FURD), was loaded in GANTREZ® AN nanoparticles only by incubating the drug with the previously formed nanoparticles and, consequently, a very low encapsulation efficiency was obtained (about 13%) [8].
With respect to the capacity of GANTREZ® AN nanoparticles to incorporate water-insoluble or poorly water-soluble molecules, it has been necessary to use complexing agents such as cyclodextrins (CDs) or solubilizers including PEG and amino acids (e.g., glycin) in order to enhance the incorporation of said type of molecules in GANTREZ® AN nanoparticles, In fact, if complexing agents or solubilizers are not used, the free drug, which is not incorporated into GANTREZ® AN nanoparticles, will precipitate as big crystals in the final aqueous suspension of the nanoparticles obtained post organic solvents evaporation under reduced pressure. Thus, the poorly water-soluble molecules encapsulation efficiency is extremely low if co-solvents are not used. Although the use of co-solvents PEG and amino acids increases the encapsulation efficacy of poorly water-soluble compounds (e.g., paclitaxel), it dramatically reduces the yield of the nanoparticles manufacture process.
GANTREZ® MS microspheres, prepared by double emulsion techniques, showed a low encapsulation efficiency of water-insoluble molecules (around 30% in case of triclosan). In addition, a rapid release of triclosan was achieved (about 100% within the first hour in PBS) which indicated the low stability of the GANTREZ® MS microsystems and the rapid drug release and/or microsystems degradation [9]. Further, GANTREZ® MS based particulate systems showed a rapid swelling in isotonic phosphate buffer (pH 7.0) (swilling half time around 10 min) and short retention times on porcine esophageal mucosa [10].
On the other hand, a very important aspect for nanoparticles production is the complexity of industrial production and scale up processes. Many techniques have been developed to prepare nanoparticles for the delivery of drugs such as emulsification or solvent evaporation techniques which involve the use of organic toxic solvents (e.g., dichloromethane, ethyl acetate, chloroform, acetone, etc.), and special complex devices such as homogenizers. The implementation of said techniques at large-scale production is still a challenge, as it requires defined steps which include process feasibility, formulation optimization, process optimization, scale-up and validation in order to develop quality products and provide a rational approach for production steps including drug concentration and polymer concentration, processing operations, particle size, drug stability or entrapment efficiency.
Although a great number of nanoparticulate systems for the delivery of products of interest based on the use of PVM/MA copolymers are known, there are some drawbacks which are still unsolved and limit their applications.
It is therefore necessary to develop further nanoparticulate systems for the delivery of products of interest which are capable of solving all or some of the above mentioned drawbacks related to the nanoparticulate systems based on PVM/MA copolymers, for example, low long-term stability in an aqueous medium, the use of cross-linkers to improve stability in aqueous media, low encapsulation efficacy for hydrophilic compounds, the use of co-solvents or complexing agents to improve the efficacy for encapsulating hydrophobic compounds, a cost and complex production process which requires the use of toxic organic solvents or complex techniques. Advantageously, said further nanoparticulate systems for the delivery of products of interest should have, in addition to high mucosal bioadhesion ability, high long-term stability in aqueous media and high encapsulation efficiency of products of interest, including oils as well as small or large, hydrophilic or hydrophobic, compounds, and/or they should be produced by more simple, environmental friendly processes. These objectives can be achieved by means of the nanoparticles provided by the present invention.